Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functionally active gamma interferon (IFN-gamma) receptors consist of an alpha subunit required for ligand binding and signal transduction and a beta subunit required primarily for signaling. Although the receptor alpha chain has been well characterized, little is known about the specific role of the receptor beta chain in IFN-gamma signaling. Expression of the wild-type human IFN-gamma receptor beta chain in murine L cells that stably express the human IFN-gamma receptor alpha chain (L.hgR) produced a murine cell line (L.hgR.myc beta) that responded to human IFN-gamma. Mutagenesis of the receptor beta-chain intracellular domain revealed that only two closely spaced, membrane-proximal sequences (P263PSIP267 and I270EEYL274) are required for function. Coprecipitation studies showed that these sequences are necessary for the specific and constitutive association of the receptor beta chain with the JAK-2 tyrosine kinase. These experiments also revealed that the IFN-gamma receptor alpha and beta chains are not preassociated on the surface of unstimulated cells but rather are induced to associate in an IFN-gamma-dependent fashion. A chimeric protein in which the intracellular domain of the beta chain was replaced by JAK-2 complemented human IFN-gamma signaling and biologic responsiveness in L.hgR. In contrast, a c-src-containing beta-chain chimera did not. These results indicate that the sole obligate role of the IFN-gamma receptor beta chain in signaling is to recruit JAK-2 into the ligand-assembled receptor complex.
Mol Cell Biol 1996 Jun
PMID:Ligand-induced assembly and activation of the gamma interferon receptor in intact cells. 864 32

Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-alpha/beta)-induced gene expression. The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3gamma protein) does not bind to the interferon-stimulated response element (ISRE). In this report, we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma. Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha. IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN. Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity.
Mol Cell Biol 1996 Apr
PMID:Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase. 865 15

A central factor in the pathogenesis of inflammatory and fibrotic lung disease (adult respiratory distress syndrome, sarcoidosis, idiopathic pulmonary fibrosis) is the locally elevated number of alveolar macrophages (AM). An elevation in the production rate of AM, chemoattraction and differentiation of monocytes, or a diminution in the death rate might be underlying mechanisms. The aim of the present study was to investigate the modulatory role of endotoxin and cytokines on the death rate of human AM. Lipopolysaccharide (LPS) treatment resulted in a 4-fold increase (7.6 to 30.2%) of AM death. AM death was apoptotic as assessed by in situ DNA end labeling (ISDE), transmission electron microscopy, DNA gel electrophoresis, fluorometry of fragmented DNA, and an ELISA specific for histone-associated DNA fragments. Among the different bacterial cell wall components tested, LPS was the only inducer of apoptosis in human AM. None of the tested cytokines (interleukin-1 beta [IL-1 beta], IL-4, IL-6, IL-10, tumor necrosis factor-alpha [TNF-alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) was capable of enhancing the spontaneous rate of apoptosis. However, LPS-induced apoptosis was significantly enhanced by the macrophage-activating cytokine IFN-gamma, and reduced by the macrophage-deactivating cytokines IL-4, IL-10, and TGF-beta.
Am J Respir Cell Mol Biol 1996 Jul
PMID:Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines. 867 23

A fast purification method for recombinant human interferon-gamma, produced in E. coli, was elaborated. Human IFN-gamma accumulated in the cytoplasm of E. coli cells as inclusion bodies (IB). After lysis, the IB were isolated from the cell debris by means of a density gradient ultracentrifugation, and solubilized in 6 M guanidine hydrochloride. The subsequent refolding step was optimized for a maximal recovery of the biologically active dimer. Refolded IFN-gamma was then purified to homogeneity in a single cation exchange chromatographic step, yielding 12.5 mg protein per liter E. coli culture. The dimeric nature of the refolded protein was visualized by means of interchain cross-linking. In a subsequent Western blot the resulting derivative was recognized by a panel of five monoclonal antibodies, indicating that those epitopes on the protein surface remained unaffected upon cross-linking.
Biochem Mol Biol Int 1995 Dec
PMID:A rapid single-step purification method for human interferon-gamma from isolated Escherichia coli inclusion bodies. 874 47

Our group has previously reported that the nuclear factor Yin-Yang 1 (YY1), a ubiquitous DNA-binding protein, is able to interact with a silencer element (BE) in the gamma interferon (IFN-gamma) promoter region. In this study, we demonstrated that YY1 can directly inhibit the activity of the IFN-gamma promoter by interacting with multiple sites in the promoter. In cotransfection assays, a YY1 expression vector significantly inhibited IFN-gamma promoter activity. Mutation of the YY1 binding site in the native IFN-gamma promoter was associated with an increase in the IFN-gamma promoter activity. Analysis of the DNA sequences of the IFN-gamma promoter revealed a second functional YY1 binding site (BED) that overlaps with an AP1 binding site. In this element, AP1 enhancer activity was suppressed by YY1. Since the nuclear level of YY1 does not change upon cell activation, our data support a model that the nuclear factor YY1 acts to suppress basal IFN-gamma transcription by interacting with the promoter at multiple DNA binding sites. This repression can occur through two mechanisms: (i) cooperation with an as-yet-unidentified AP2-like repressor protein and (ii) competition for DNA binding with the transactivating factor AP1.
Mol Cell Biol 1996 Sep
PMID:The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. 875 32

Gamma interferon (IFN-gamma) signals to the nucleus through the activation, by tyrosine phosphorylation, of the latent cytoplasmic transcription factor Stat1 (signal transducer and activator of transcription). It has been demonstrated that the activity of Stat1 is dependent on tyrosine phosphorylation which is regulated by Jak tyrosine kinases as well as by the as-yet-unidentified protein tyrosine phosphatase. We report that the N-terminal domain of Stat1, which is highly conserved among all STAT family members, is required for its tyrosine dephosphorylation. A single amino acid substitution (Arg-31 to Ala) in the Stat1 N-terminal domain inhibited Stat1 tyrosine dephosphorylation. The deletion of the Stat1 N-terminal domain resulted in a mutant Stat1 protein which was constitutively phosphorylated on Tyr-701. Upon IFN-gamma stimulation, the tyrosine phosphorylation of this mutant protein was further enhanced but was not down-regulated by protein tyrosine phosphatase in vivo. When expressed in NIH 3T3 cells, this mutant protein greatly enhanced the antiproliferative activity of IFN-gamma. We suggest that the N-terminal domains of STATs are crucial for modulating STAT activities through regulating the tyrosine dephosphorylation of STATs.
Mol Cell Biol 1996 Sep
PMID:Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. 875 52

Peptides eluted from murine Major Histocompatibility Complex (MHC) class II molecules are predominantly fragments of self proteins, which include apolipoprotein E, cystatin-c, transferrin receptor, MHC class II and Ii chains. These naturally processed self peptides are expected to be presented during ontogeny. Therefore, immune responses to these peptides in syngeneic hosts may be under physiological control so as to modulate auto-reactivity. As would be expected from our current understanding, T cells reactive to such antigens should be deleted or clonally anergized. To explore this possibility, we investigated the immunogenicity of a number of these self peptides in mice that express MHC class II, from which these peptides were eluted. T cell and antibody responses were measured following immunization of mice with the appropriate peptide. Surprisingly, many of these peptides were highly immunogenic in normal mice. T cells reactive to these self peptides are restricted by syngeneic MHC class II and were blocked by alpha CD4 antibodies. T cells primed with the native protein in vivo could be challenged with the appropriate self peptide in vitro. Some of the self epitopes induce Th1 cells as indicated by IFN-gamma but not IL-4 production and others induce Th2 cells. Antipeptide antibodies were detected only at higher doses of antigen. Our results suggest that T cells specific for many of the naturally processed self peptides are not deleted but tolerance to these peptides is still maintained in vivo. Presumably the high-affinity self-reactive T cells are deleted in the thymus and the low-affinity self peptide reactive T cells remain unresponsive to antigen challenge in vitro. Upon antigen priming in vivo, many of these self-reactive T cells become activated and readily respond to antigen challenge in vitro. These results point to the physiological control of the maintenance of tolerance to naturally processed self peptides.
Mol Immunol
PMID:Immune responses to self peptides naturally presented by murine class II major histocompatibility complex molecules. 876 Feb 74

Apoptosis is a common pathway by which cells respond to noxious insults or growth regulatory factors. Since cellular glutathione (GSH) content has long been known to govern response to antineoplastic treatment we have compared induction of apoptosis in drug sensitive (HL-60 and K562/WT) and drug resistant (KG-1a and K562/ADM) human leukemic cell lines by the monoclonal antibody CH-11 (anti-Fas/Apo-1). Fraction of apoptotic cells and cellular GSH were determined by flow cytometry. All cell lines were induced to undergo apoptosis by exposure to mAb CH-11 independent of resistance to conventional antineoplastic treatment. In conjunction with exposure to daunorubicin, vincristine, carboplatin, cytosine arabinoside, dexamethasone, or ionizing irradiation the effect of mAb CH-11 on induction of apoptosis was no more than additive. In contrast, preincubation with IFN-gamma markedly enhanced the induction of apoptosis by mAb CH-11 due to an increase of Fas-receptor expression. In each instance, GSH content decreased with increasing fraction of apoptotic cells indicating a crucial role of GSH in the apoptotic pathway.
Blood Cells Mol Dis 1996
PMID:Anti-Fas/Apo-1 monoclonal antibody CH-11 depletes glutathione and kills multidrug-resistant human leukemic cells. 880 81

To assess whether Th-2 cytokines are involved in the late airway response (LR) after antigen challenge, we evaluated cytokine mRNA expression in the lungs of two strains of rats before and 8 h after saline or antigen challenge: Brown Norway (BN) rats, high IgE producers that develop LR after antigen challenge and Sprague-Dawley (SD) rats, low IgE producers that develop little LR and no increased airway responsiveness after antigen challenge. Rats were sensitized with ovalbumin (OA) and 14 days later, lungs were obtained before or after OA challenge and measurement of lung physiology for 8 h. Lung tissue was either fixed for in situ hybridization or frozen for evaluation of mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). We examined mRNA expression for interleukin-4 (IL-4), and IL-5 (Th-2 cytokines) and IL-2 and interferon gamma (IFN-gamma, Th-1 cytokines). In situ hybridization showed that cells expressing IL-4 and -5 mRNA were increased in the airways of the lungs of BN rats after OA challenge (P < 0.05) and that cells expressing mRNA for IFN-gamma and IL-2 were higher in SD than in BN rats after antigen challenge (P < 0.05). Results from PCR showed that prior to antigen challenge, BN rats expressed in their lungs mRNA for IL-4 and -5 and SD rats expressed very little mRNA for IL-5 only. After antigen challenge most BN and SD rats expressed mRNA for IL-4 and -5 but expression of mRNA for IL-2 and IFN-gamma was only found in SD rats. In conclusion, rats that develop a LR after antigen challenge preferentially increase Th-2 cytokine expression in their lungs whereas those without LRs preferentially express Th-1 cytokines. Our results support the role of Th-2 cytokines in the LR and asthma.
Am J Respir Cell Mol Biol 1996 Sep
PMID:Cytokine expression in the presence or absence of late airway responses after antigen challenge of sensitized rats. 881 Jun 41

Pulmonary inflammation is characterized by the accumulation of eosinophils and other leukocytes in the lungs of individuals challenged with antigen. Cytokines released by the Th2 lymphocyte subset, especially interleukin-4 (IL-4) and interleukin-5 (IL-5), are also present and thought to play an important role in this process. Previously, we used a model of aerosolized antigen challenge of sensitized mice to show that T cells were necessary for the accumulation of eosinophils and the production of cytokine steady-state messenger ribonucleic acid (mRNA). T cells were isolated from lung tissue at a time (4 h) when high levels of IL-4 and IL-5 mRNAs had accumulated, and from bronchoalveolar lavage fluid (BALF) and lung tissue at a later time (24 h), when inflammation could be detected by lavage. Lung-derived lymphocytes from sensitized challenged mice consisted of approximately 40% Thyl+ T cells (20% CD4+, 13% CD8+, and 6% CD4+/CD8+) and 30% B220+ B cells. Both BALF- and lung-derived T lymphocytes exhibited a similar activated/memory phenotype (CD44+ CD45RBlo), although lung tissue also contained less differentiated cells (CD44+ CD45RBhi). Thyl+ BALF cells isolated by magnetic bead-mediated separation accounted for approximately 88% of the IL-5 mRNA, 21% of the interferon-gamma (IFN-gamma) mRNA, and < 2% of the IL-4 mRNA detected in unseparated samples by reverse transcriptase-polymerase chain reaction (RT-PCR). Thyl+ T cells from lung tissue accounted for approximately 98% and 89% of IL-5 mRNA, 56% and 80% of IFN-gamma mRNA, and 23% and 40% of IL-4 mRNA at 4 h and 24 h after challenge, respectively. These experiments demonstrate that isolated T cells from BALF and lung are responsible for most of the IL-5 mRNA, but not all of the IFN-gamma or IL-4 mRNAs, detected in this model. These results are consistent with human studies indicating T cells as the major source of IL-5 mRNA in the lungs of asthmatic patients.
Am J Respir Cell Mol Biol 1996 Sep
PMID:T cells are the predominant source of interleukin-5 but not interleukin-4 mRNA expression in the lungs of antigen-challenged allergic mice. 881 Jun 48


<< Previous 1 2 3 4 5 6 7 8 9 10